Newly identified potential therapeutic approach kills triple-negative breast cancer cells in pre-clinical study

Findings suggests potential new area of focus for checkpoint blockade immunotherapy

MD Anderson News Release February 12, 2018

Triple-negative breast cancer (TNBC), a highly aggressive, relapse-prone cancer that accounts for one-fourth of all breast cancers, could be the focus of a new area of study for immune checkpoint blockade therapy.  A team of researchers at Â鶹ӳ»­ MD Anderson Cancer Center revealed that in TNBC a cell process called glycosylation is required for PD-L1/PD1 molecules to interact and identified exactly how and why glycosylation is so crucial. Findings from the study were published in the Feb. 12 issue of .

Immune checkpoint blockade therapy relies on connections between PD-L1 and its sister molecule, PD1, found on T-cell surfaces, allowing cancer cells to go undetected by the immune system. Blocking PD-L1 and PD-1 interaction has been the basis for successful immunotherapies already in use in other cancers.

¡°Glycosylation is a process that attaches portions of sugar molecules called moieties to the protein providing it fuel to grow and spread,¡± said Mien-Chie Hung, Ph.D., chair of Molecular and Cellular Oncology. ¡°Glycosylation of PD-L1 in tumor cells stabilizes PD-L1, but it is largely unknown whether sugar moiety by itself is required for binding to PD-1 to suppress anti-tumor immunity.¡±

Hung¡¯s research group shed further light in this area through discovery of glycosylated PD-L1 (gPD-L1), and worked with STCube Pharmaceuticals, Inc. to develop anti-gPD-L1 antibodies that recognize this glycosylated form of PD-L1, killing tumor cells while not harming healthy ones.

To improve the therapeutic efficacy of anti-gPD-l1 antibody, the team linked a potent small molecule chemotherapy agent, called MMAE, to the anti-gPD-L1, creating a new antibody drug conjugate (ADC), called anti-gPD-L1-MMAE, which resulted in higher therapeutic efficacy in animal models. Hung believes the development of this glycosylated PD-L1 ADC (anti-gPD-L1-MMAE) may represent a new generation of immunotherapy that is more targeted with fewer adverse effects.

¡°We demonstrated that gPD-L1 is an excellent candidate for ADC as sugar moiety is critical for PD-L1¡¯s detrimental role in TNBC,¡± said Hung. ¡°Immune checkpoint blockade treatment options remains limited in TNBC, so identifying new immune checkpoint targets to improve upon current therapy is urgently needed.¡±

MD Anderson study participants included: Chia-Wei Li, Ph.D.; Seung-Oe Lim, Ph.D.; Jun Yao, Ph.D.; Jong-Ho Cha, Ph.D.; Weiya Xia, M.D.; Li-Chuan Chan; Taewan Kim, Ph.D.; Shih-Shin Chang, Ph.D.; Heng-Huan Lee, Ph.D.; Chao-Kai Chou, Ph.D.; Jennifer Hsu, Ph.D.; Jung-Mao Hsu, Ph.D.; Hirohito Yamaguchi, D.V.M., Ph.D.; and Tzu-Hsuan Huang, Ph.D., all of the Department of Molecular and Cellular Oncology.

The study was funded by the National Institutes of Health (CCSG CA16672 and R21 CA193038); the Cancer Research Institute of Texas (RP160710); the National Breast Cancer Foundation, Inc.; the Breast Research Foundation (BRCF-17-069); the Patel Memorial Breast Cancer Endowment Fund; Â鶹ӳ»­ MD Anderson-China Medical University and Hospital Sister Institution Fund; the Ministry of Science and Technology, International Research-intensive Centers of Excellence in Taiwan (I-RiCE and MOST 105-2911-1-002-302); China Medical University Hospital Cancer Research Center of Excellence (MOHW106-TDU-B-212-144003); the Center for Biological Pathways; the Susan G. Komen for the Cure Postdoctoral Fellowship (PDF122311298); and the National Research Foundation of Korea (MSIP, NRF-2011-357-C00140 and2011-030001).